Monoalkyl ethers of diethylstilboestrol



Potente Sept. '25, i

' Ebveiwer met d & Tie

ore,Md., atolls-nor to note, a, Belicville,

N. corporati f New .1

No Dre. hpplication Tune 25, will, 80 No. Mtfidl 2 it' This inventionrelates to monoalkyi ethers and the method of making'them. Moreparticularly,

the. invention relates to medicinal compositions including the monoalkylethers of stilboestrol or like compounds.

The monoalkyl ethers are adapted especially for use in producing thephysiological eflects oi a female sex hormone. The invention will be i1-lustrated, therefore, by description of ethers characterized byoestrosenic activity.

A great deal of research has been carried out on the production ofsynthetic materials having properties similar to those, of oestrin ortheelin, a naturalfemaiesex hormone concerned in the oestrosenic cycle.There has been made and sold for this purpose, for instance.diethylstilboestrol, which is the alpha-beta-diethyl4,i'-dihydroxystilbene. This compound when used in quantity sumcient tocause oestrus frequently pro" duces also undesired toxic eiiects. Itsuse is second panied or followed in many instances by nausea orheadache, In fact, in one study it was found that 11 of 18 patientsgiven diethylstilboestrol showed toxic eilects: doses of 0.8 to 3.0 mgi'or various periods of time, produced in ii of the patients severenausea and continuous vomiting, followed by complete gastric intolerance(Dodds, of the Courtaulds Research Institute, writing in Lancet, 296,1939, I). Furthermore, it is not Diethylstilhccstrol, for example, iscommonly represented by formula (A):

CaHa CsHa My new ethers may be repTes%d, A the type formula (B) w c f inthe formula (B), R and R represent all'rvl groum and R a monovalenthydrocarbon radical, suitably a primary alkyl group, although branchedto chain, secondary, cyclic, and either saturatedor group (R for thehydrogen atom of one of the hydroxyl groups. A second diflerenoe is-thereplacement of the ethyl groups in the alpha and heta positions indiethylstilboestrol by alkyl groups R and R that may or may not be theethyl t5 radical.

When. the monoalkyl .ethers of the type formule (B) are to be used togive maximum oestro- Eeenie effect. then R and Rishould be ethyl. B

should be a short chain alkyl radical, containing feasible to controlthe extent of the physiological 30 buy 1 t w Moms. if it is desired to Peii'ect produced by diethylstllboestrol.

It is anpobiect of the invention to provide a material of satisfactoryoestrogenic potency which does not possess the toxicity oioliethylstilboestrol.

Another object is to produce a composition adapted to produce oestrusfor a period of time that is controllable by the dosage of thecomposition- These and such other objects of the invention as willappear from the detailed description that follows are secured by meansof the composition and method described.

Stated briefly, my invention comprises monoalkyl ethers ofdlalkylstilboestrol. The inven-. tion comprises also the method ofmaking such ethers and medicinals comprising them.

The general relationship of my new class, of compounds to thedialkylstilboestrols will be evident from a consideration of formulasthat may be used to represent the related compounds.

duce the oestrogenic eflect with as small a dose as possible. desirableand in such circumstances a longer chain alkyl group may be used inposition R Like-.

85 wise, the R and R groups may be methyl or propyl or other alkyl iithe attendant loss in oestrosenic potency is not objectionable.

It will be understood that R R, and It may all represent the same alkylor different alkyls within the range of carbon atoms given above foreach position of they alkyl group. Thus, R may be methyl, R ethyl, and Rmethyl or ethyl.

In making the new series of monoalkyl others,

tion oi an alpha, beta dialkylstilboestrol. More specifically, themethod is one which comprises .the step of replacing the hydrogen of onebydroxyl group of the dialkylstilboestrol by an alkyl However, this/maynot always be the general method used is that of partial alkylenunis"eflectedx'byi.heatingszaniaqueousi'alcoholicrsolw l tion or itcontaining *potassium or sodium hydroxiderand'ithe halide or theselected alkyl. :By

using rone 1 equivalent, for I alkali i and one 101 the r halide, .themonoalkyl :ether 1 is #:obtained :as the predominating taken :of thefact @thatxthe -monoalkyl .ethers: are

much -less soluble .in- :5dilute alcoholic. alkali athan :isalpha,.:betadiethylstiiboestrol.

The 'materiais are maintained' in intimate coneach other "for asubstantial period of "timepthe temperature lbcinsckeptlbelow, the boil-..product. Advantage .may :be

The alpha. betadialblstilboestrol is dissolved in alcohol, the alcohol.bein: warmed slightly it necessary :to effect-solution.Waterandpotassiumhydroxide'areaddedgthe temperature of the mixture.beinglrepthelow' the boiling pointof the alkylhalide to be added. Thealkylhalidetis then added.

Alkylether Methyl n-Am'yl n-Heptyl Dieth lstllboestrol. 1 gram. 1 gram.1 gram.

'Potml umhydroxideunlequivalentn, lequivalent iequivaleut. X351 s im) gm(m s O cc- 0 I B co. I Ailryl halldedn exeess.... Mel -AmB n-He. inTemperature; 90. Time 10.5 hours.

Yield 'di (crude)- Yield mono (crude) 7 P. mono I 86.6. .P. at 23 04.8"49.5". OeetIOBBH-Ic activity ilgamma About gamma" About 60 gamma.

1 Specimen probably contained a small proportion of di-arnysl ether.

v i 1 Weight required to produce oestrous in ovari ing point of. theselected "halide, but in any ss,

nothigherithan about 80 C. "Evaporatien'is prevented by eitherv closingthe yess'eltig'htly or using a reflux condenses,

ixture stands :under the; conditions described,a substantial portionrofcrude monoether. separates asan undissolved i product. The whole productis 'precipitatedbythe addition of water and separated, as by filtration,and repeatedly washed or extractedwitlr aqueous-solutions or alcohol andan alkali .metalhydroxide otsuch oi crude mono-ether Whenthe reaction iscompleted a large amount zusually crystallizes out. An excess or water.is now added which precipitates the balance or the products from thesoluconcentrations as to dissolve 'very littlev of the monoetherainproportion :to .the solvent power for remainingrraw materialsused ineffecting the reactionxonior undeslredhyaproducts. Finally themonoalkyl- :etheriis: dissolved in warm alcohol to give ea nearlysaturated solution. Any :undissolved material present is. separated byfiltration or 'decantation, andthe resulting solution of themonoalkyletherris"allowed-to :cool, to cause crystallization."Thecrystalsrsoaobtained may'berecrystallized by repeating theoperation.

In chocsingthe :proportionrot alcohol to water in the medium io'r theinitial reactiondescribed above :orfior washingv sand extracting .the'monoalkyl ether-i first formed, .-:the proportion of. alcohol .to wateris made relatively lowwhen the radi-' cal R3. is. methyl Lot ethyl.Thudxinusingmethyl or ethyli'halidesiini-the:aboverreactiomthe'proportion:of alcohol: may be "approximately 1 part byvolumestoflapartskotwater. :In making the compoundszof: the same"type,'"but.with halldesof alkylradicals containing :3'or morezcarbon'atoms,

theproportionof alcohol is increased more or less 1 in proportion'tothesize otthe'alkyl groupwhich is to be introduced into the'idialkylstilboestrol. Thus, when 'the 1 alkyl .halide -.used includesan alkyl radical containing i .18 1 carbon atoms, .there is usedalcoh'olzof.concentrationabout 94 per cent by volume. In" this caselthereaction is-allowed to proceediorxseveral. days *at approximately 40 C.or higher, aiter'which the alcoholic medium is dilutedwith water to.cause precipitation oithe monoalkyl ether. p

Detailed examples otthe preparation 0! the monoethers are givenbelow.

tion and they are-separatedbyiiltration. .Aiter drying, .theflltericake' isdissolved in a small amount of alcoholpone halt theamount of potassium hydroxidein concentrated aqueous solution originallyusedaisadded and the mixture is allowed to cool :slowly. .1! thecorrectamount oi -water-has been usedto dissolve the potassium hydroxidethe di-ether-tormedz-wiil be insoluble in the cold dilute alcohol andwill crystallize out. This is then removedby filtration. It the'dietheris present in only a small quantity or it in sufllcient water hasbeenaddedto the potassium hydroxide, it may be necessary to addadditional small quantities or water to'the hot solution until a faintcloudiness indicates that the di-ether is insoluble even in thehot.solution. lUpon cooling the di-ether will'then crystaliizeout, and isremoved by. filtration. :To the filtrate further quantitiesoi :water areaddedrwhich will now precipitate the mono-ether. This again is removedby flltration.- Fromthe flnakflltrate'unreacted "stilboestrol can berecovered by acidification.v

The crude mono-ethenwhlch is obtained as'above is purified by repeatedfractional-crystallization -usingmethyl and 'ethylwalcoholalternatively.

The recipitate is sometimes otslimy-consistency, particularly it it hasbeen'obtained by further dilution of the alkaline aqueous alcoholsolution with water. It can be-readily eonvertedintoa crystalline statei! it is orystallize'd'irom'pure or the precipitate, is .used. The wholemass'ls dissolved. Traces of di-ether=are permitted to crystallize out,as indicated above: the monoother is again precipitated by'dilution'andthe accuse 3 remaining stilboestrol recovered by acidification oi thefinal filtrate. As a third solvent acetone is also useful.

The mono-ethers oi alpha, beta clialkyl stilboestrol so prepared showgreat dlflerences in potency from the di-ethers. In fact, the doserequired of the di-ethersvaries from 30 to 100 times the quantity whichis adequate for the mono-' ether. The di-ethers may be considered asderived from compounds of the type represented in formula 3 above byreplacing the hydrogen of the hydroxyl group with an alkyl group.

The mono-ethers are not only potent but when administered inphysiological doses do not ordinarily cause nausea and headache; whichare undesirable characteristics of diethyl-stilboestrol. Furthermore,when administering the monoethers variation of the dose permits controlof the duration of oestrus. Increased doses prolong the oestrus. This isa characteristic property oi the mono-ethers. When administeringdiethyl-stilboestrol, a larger dose than necessary to produce oestrusonly increases the undesirable manifestations o1 headache and nausea.

The method of testing for oestrogenic efl'ect is that which is standardin the biological assay of the natural female sex hormones; This test isapplied to a number of ovariectomized rats, guinea pigs, or mice. Ratswere used by me. The selected animals were given injections 01 variousdilutions of the composition to be assayed. The vaginal epithelium wasthen examined to determine the condition.

An unknown material or extract is said to contain, for instance, 1,000rat units to the gram or cubic centimeter, if one-thousandth of a gramor of a cubic centimeter is Just sufllcient to produce oestrus in theovariectomized animals, whereas half as much of the compound is notadequate to show the oestrogenic efiect.

It will be understood that, in such assays, the accuracy is not as highas in an ordinary chemical analysis or physical determination. Withinthe customary limitations of bioassay methods, however, these valueshave been checked by other investigators. At any rate, it is certainthat the melting point checks approximately that for a' given monoalkylether, a second alkyl group of the same kind may be introduced and themelting point then compared with the corresponding diether. Meltingpoints for a number oi the monoand diethers of diethylstilboestrol aregiven in the above table in form suitable for usefor this purpose.

The introduction of the second alkyl group into the monoether, to givethediether for p rposes of identification, may be made in conventionalmanner.

' The term diethylstilboestrol" is used herein to designatealpha.beta-diethyl 4.4'-dihydroxystilbene unless otherwise specificallystated.

It will be understood that the details given are for the purpose oiillustration, not restriction, and that variations within the spirit ofthe invention are intended to be included in the scope .of the appendedclaims.

What is claimed is: 1. A chemical compound of the type formula 02H:Calls o 0 in which R consists of the methyl radical. 2. A chemicalcompound oi the type formula D o r

